CN1705683A - Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives - Google Patents
Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives Download PDFInfo
- Publication number
- CN1705683A CN1705683A CNA200380101570XA CN200380101570A CN1705683A CN 1705683 A CN1705683 A CN 1705683A CN A200380101570X A CNA200380101570X A CN A200380101570XA CN 200380101570 A CN200380101570 A CN 200380101570A CN 1705683 A CN1705683 A CN 1705683A
- Authority
- CN
- China
- Prior art keywords
- taxan
- hyaluronic
- derivatives
- hyaluronic acid
- spacer molecule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 162
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 81
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- 229940123237 Taxane Drugs 0.000 title abstract 5
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- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 claims description 4
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 claims description 4
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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Abstract
The present invention relates to water-soluble taxanes covalently bounded tohyaluronic acid or hyaluronic acid derivatives, and in particular to paclitaxel and docetaxel, useful for the preparation of pharmaceutical compositions to be used in the field of oncology, in the treatment of autoimmune disorders and of restenosis. The invention also relates to the process for preparing taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives by direct synthesis between molecules of hyaluronic acid and of taxane or by indirect synthesis by the introduction of a spacer between the hyaluronic acid or hyaluronic acid derivative and the taxane.
Description
Technical field
This invention relates to Taxan, relates in particular to taxol and Docetaxel with hyaluronic acid or derivatives of hyaluronic acids covalent bonding, and their reparation technology and in the use in oncology, autoimmunity imbalance and treatment of restenosis field.
Background technology
Taxan, particularly taxol and Docetaxel are at present with Taxol
And Taxotere
Trade(brand)name sell, be anticarcinogen (Huizing M.T. etc., Cancer Inv., 1995,13:381-404), they are brought into play antiproliferative by the tissue of the microtubule in the cell skeletal system that acts on cell and give birth to effect.By suppressing the unpolarizing of described microtubule, their stop the normal dynamically re-organized effect that takes place in cell mitogen (Manfredi J.J. etc., JCell Biol, 1982,94:68-696).
The main treatment indication of taxol is as follows:
-treatment advanced breast cancer;
-treatment Kaposi;
-treatment lung cancer (non-small cell knurl);
-the conventional chemical therapy there is an ovarian cancer of resistance.
In addition, described chemotherapy also is used for bladder cancer, prostate cancer and treatment of endometrial cancer.
Determine that taxol is water insoluble, it and polyoxyethylenated castor oil (Cremophor
EL) 1: 1 mixed of (Viscotrol C) ethanol be used at present the pharmaceutical composition of cancer chemotherapeutic (people such as Pfeifer R.W., Am.J.Hosp.Pharm., 1993,50:2520-2521).This prescription is generally used for successive intravenous drip (between 3-24 hour), and dosage is 135-175mg/m
2
In above-mentioned prescription, Cremophor
The existence of EL is the major cause that causes untoward reaction, takes place in the taxol medication as this undesirable action.From urticaria takes place to expiratory dyspnea and bronchospasm, even, anaphylactic shock (Weiss, R.B. etc., J.Clin.Oncol, 1980,8:1263-1268).
Therefore, prepare to accept taxol-polyoxyethylenated castor oil (Cremophor
The patient of medicine composite for curing EL) at first must take the premedicate scheme, takes dexamethasone, may also will be used antihistaminic agent.
Although these preventive measures are arranged, still stood light or heavy untoward reaction up to 40% patient who accepts the administration of taxol intravenous drip.
Therefore we can say the Tyke rope (Taxol of present clinical use
) prescription and the medication used thereof, constituted the restriction of its effect.The reason that Here it is will carry out the synthetic and/or new chemical formulation research of new formula of medicine now to water miscible above-mentioned cancer therapy drug.
For example, the researchist has attempted taxol is packed into by liposome, Nano capsule and the microsphere of biodegradable multipolymer (as poly(lactic acid)) and the formed polymer wall formation of not biodegradable multipolymer (as ethylene-vinyl acetate).
In addition, also prepared the microsphere that taxol is housed, formed by biodegradable polymkeric substance (as poly phosphate), like this, produce system (Nui jen, the B. etc. of the permanent release medicine in a kind of lung cancer therapy, Investigational New Drugs, 2001,19:143-153).Also attempt by in organic solvent with phosphoric acid fat choline/cholate coprecipitation taxol prepare described anticarcinogen micella (Nui jen, B. etc., Investigational New Drugs, 2001,19:143-153).
But, these new systems that are used for packing taxol in stability, produce and heavily can get into trouble aspect the property seen.
And, also make many effort and dissolve this medicine with cyclodextrin, still, new prescription do not produce desired 1 result (Nui jen, B. etc., Investigational New Drugs, 2001,19:143-153).
Not only made that medicine was more water-soluble, but also keep the chemical research of the new prescription of taxol of anticarcinogen validity, and caused the new analogue synthetic (United States Patent (USP) 2001/0018531) modified in C2 ' and C7 position, and prepared new prodrug.
Prodrug is an inert medicaments derivative on the curative effect, and they are introduced in the body postactivated.Spontaneous hydrolysis and (or) after the enzymatic degradation process, discharge active ingredient.
In view of this, and above-mentioned reason, make many effort and synthesized new prodrug.For example, medicine (Mellado, W. etc., Biochen have been prepared as the acetyl taxol, Biophys, Res.Commun, 1984,124 (2): 329-336), perhaps, on the carbon of C2 ' position, carry out new ester class with succsinic acid, L-GLUTAMICACID and sulfonic acid and said medicine and synthesize.But these ester classes show unstable under water surrounding.
In addition; also synthesized have in C2 ' or C7 position phosphinylidyne oxygen base phenylpropionic acid ester group because of some derivatives (as taxol-2 '-carbonic ether), and the amino acid esters of a series of taxols and their derivative that has glutaryl-group in C2 ' position.
Glutaryl-taxol l-asparagine and glutaryl-taxol glutamine has proved the highest water-soluble product that obtains with above-mentioned synthetic method, but they are than the effect of taxol itself poor (Nui jen, B. etc., Investigational New Drugs, 2001,19:143-153).
Also know taxol with poly--L-L-glutamic acid esterification, generate the new soluble derivative of described chemotherapeutic, it significantly improves (Li, Cancer Research such as C., 1998,58 (11): 2404-2409) than the blood plasma half life of the non-taxol of puting together.
Also by in C2 ' position by this chemotherapy drugs of esterification, make the taxol derivatize with PEG (polyoxyethylene glycol).But, though that new molecule has shown is very water-soluble, less stable.
Recently, put together, developed a kind of new delivery system of this medicine by taxol and human serum albumin (HSA).The conjugate of taxol-HSA is very water-soluble, and can carry the most nearly molecule of 30 these chemotherapeutics.But, show that in the external experiment of carrying out it is not so good as taxol itself to the resistant function of cancer.(Nui jen, people such as B., Investigational New Drugs, 2001,19:143-153).
Recently, the researchist makes paclitaxel ester with the hyaluronic acid of modifying in advance (to call " HA " in the following text), has synthesized a kind of new delivery system, i.e. HA and carboxyl bonded hydrazides molecular reaction (Luo by amido linkage and HA, Y. wait Biomacromolecules 2000,1 (2): 208-218); U.S. Patent number 5,874,417.The delivery system that taxol is new makes the directly surface of cell membrane of target approach cancer cells of medicine, is feature with the overexpression of HA acceptor (CD44).The result confirms, can combine with the CD44 of cancer cells with taxol with the functionalized HA bonding of hydrazides professionally, therefore can (by the endocytosis process) enter tenuigenin, in tenuigenin, it can be released by the effect of enzyme and activate, and inspires the depolarize and the fissional restraining effect of tubulin.The mechanism of this selectivity transmission of this medicine is called " cell-targeting " (" cell targeting ").
In addition, we know, HA is in pharmaceutical composition, can be used as the vehicle of cancer therapy drug, wherein HA and chemotherapeutic medicine (as taxol) associate (non-covalent bonding), because above-mentioned target phenomenon, thereby increase curative effect (international patent application no WO 00/41730), thereby the increase curative effect, and can reduce the dosage (international patent application no WO 99/02151) that the conventional chemotherapy scheme is stipulated.
Recently, know, with low-molecular-weight HA and (or) lipid derivate can be used to produce and is used to transmit medicine, comprises the liposome (international patent application no WO 01/39815) of cancer therapy drug (as: taxol).
In sum, still need stable and tool water-soluble, and curative effect reaches the novel taxane derivative of the Taxan of unmodified at least.
Summary of the invention
The applicant has been found that, randomly use spacer molecule (spacer) (spacer), with derivative covalent bonding with Taxan and HA or HA, can obtain stable, water-soluble articles, useful for producing of the medicine of the treatment of treatment tumour, autoimmunity imbalance and restenosis.
Therefore; the theme of this invention is; the Taxan that closes with HA or HA derivative covalence key; wherein covalent linkage is at the hydroxyl of Taxan and the carboxyl of HA or HA derivative; or form between the amino of the HA of deacetylate; randomly by spacer molecule with the Taxan chain to HA or HA derivative, condition is that described spacer molecule is different with hydrazides.
This invention also relates to the technology of producing with the Taxan of HA or HA derivative covalent bonding.
Further theme of the present invention is, comprises the pharmaceutical composition of the Taxan of at least a and HA or HA derivative covalent bonding as active substance, and their uses in the treatment of tumour, autoimmunity imbalance and restenosis.
The Taxan that closes with HA or HA derivative covalent bond of the present invention has many advantages, is summarized as follows:
1) their dissolvings rapidly in blood flow;
2) when the preparation prescription, they do not need and polyoxyethylenated castor oil (Cremophor
El) mix, so just overcome above-mentioned problem about supersensitivity and anaphylaxis;
3) owing to the enzymatic action of the enzymes such as esterase that exist usually in the blood plasma, Taxan is discharged into rapidly from the present composition in the blood by their vehicle HA or HA derivative, and they can freely bring into play their antitumous effect in blood.
4) they can produce a kind of new medicine, and in the cancer of some kind, these medicines are amazingly bigger than the chemical curative effect that non-conjugated Taxan obtained of taking same dose.
Description of drawings
Fig. 1 has shown the per-cent (black histogram) in contrast of surviving after the tumour cell described in the embodiment 1 is implanted, and accept taxol (grey histogram) and accept 16% esterification that embodiment 7 produces, with the survival per-cent (white histogram) of the mouse of the taxol of HA covalent bonding.
Fig. 2 shown with IC50 represented and from embodiment 2 experiment was drawn, with the taxol of the ester derivative covalent bonding of the HA with 16% esterification (grey histogram), 22% esterification (black histogram) and 6.8% esterification (white histogram), to four pharmacological effects that clone is compared with reference goods taxol of mammary cancer.
Fig. 3 shows that embodiment 3 is described in control mice (dotted line) with accept ACP
In the mouse of gel (solid line), the survival per-cent after tumour cell is implanted.
Fig. 4 shown with embodiment 7 in the preparation with HA ester covalent bonding, be discharged into embodiment 13 described per-cents with respect to the taxol in the human plasma in the test of time.
Embodiment
This invention has been described the compound that belongs to Taxan family, more preferably respectively with molecular formula (I) and (II) represented taxol and Docetaxel, they and HA or HA derivative covalent bonding, preferably with the method for spacer molecule, with these two molecule covalent bondings as the interface between Taxan composition and HA or the HA derivative.
HA is a kind of mixed polysaccharide, is made up of the alternately residue of D-glucuronic acid and N-acetyl-D-glucosamine, contains following repeating unit:
HA is a kind of linear chain polymer, and its molecular weight is 50,000 and 13 * 10
6Do not wait between the Da, decide on its source and acquisition methods.It is present in synovia, vitreous humor and the umbilical cord in base substance (being one of its main component), joint of pericellular gel, vertebrates reticular tissue at occurring in nature.HA plays a significant role in the tissue of biology, for many tissues, as: cells such as skin, key, muscle and cartilage play the effect of mechanical support.It is the main component of extracellular matrix, but it has other function, as: the hydration of tissue, lubricated, cell migration and differentiation.
The HA that is used for this invention can extract from any source, for example, from the cockscomb of cock, by fermentation, perhaps obtains by other processing method, and its molecular weight is 400 and 3 * 10
6Between the Da, particularly 400 and 1 * 10
6Between the Da, be preferably 400 and 230, between the 000Da.
According to this invention, the HA derivative is preferably chosen from following HA derivative.
-with organic bases and (or) the salifiable HA of mineral alkali shape;
-Hyaff
: (being incorporated herein by reference) of in U.S. Patent number 4851521, disclosing, the HA ester class that forms with the alcohols of aliphatics, araliphatic (araliphatic), alicyclic, aromatic series, cyclic and heterocycle series, its degree of esterification is along with the type of employed alcohol and length and change, have in no instance and surpass 50% gamma value, best between 0.1-20%, because the final polymkeric substance that obtains must be water miscible, and nonesterified HA remainder per-cent may with organic bases and (or) mineral alkali forms salt.
-Hyadd
TM: (being incorporated herein by reference) of in european patent number 1095064, disclosing, the HA amide compound that forms with the amine of aliphatics, araliphatic (araliphatic), alicyclic, aromatic series, cyclic and heterocycle series, its amidation degree is between the 0.1-10%, because the final polymkeric substance that obtains must be water-soluble, and not the remainder of amidated HA may with organic bases and (or) mineral alkali forms salt.
-according to U.S. Patent number 6,027,741 (being incorporated herein by reference) of disclosing, O-sulfated derivative HA, its degree of sulfation are the 4th degree;
-ACP
: (being incorporated herein by reference) of in european patent number 0341745B1, disclosing, it must be water miscible as polymkeric substance that gamma value is no more than 15% HA lactone, the gamma value that preferably has 0.05%-10%, the remainder of nonesterified HA may with organic bases and (or) mineral alkali forms salt.
The deacetylate compound of-HA: they are derived from the deacetylation of N-acetyl-glucosamine; deacetylation percentage ratio is preferably between 0.1-30%; and the carboxyl of all HA can with organic bases and (or) mineral alkali forms salt, as with shown in the following structure (A):
The deacetylation compound of HA is disclosed among the international patent application no WO 02/18450, and we are incorporated herein by reference it.
-Hyoxx
TM: the full carboxylation HA derivative that the oxidation by the unitary elementary hydroxyl of N-acetyl-glucosamine obtains, full carboxylation degree is 1 to 100%, is preferably 25 to 75%.The whole carboxyls of HA can with organic bases and (or) mineral alkali forms salt, shown in following structure (B):
Complete carboxylated HA derivative is disclosed among the Application No. US2003181689.
In addition, existing wherein Taxan, especially taxol, with the compound of HA ester class covalent bonding, the HA molecule of chemically modified never begins, only after synthetic with chemotherapeutic medicine, by with the esterification of above-mentioned all alcohols, the HA modification is obtained Hyaff
Product, perhaps, at ACP
Situation under, then form lactone (seeing embodiment 8).
The HA derivative that the front is listed; at prodrug HA-Taxan; particularly be even more important in the synthesis technique of prodrug HA-taxol; these derivatives are sulfated derivatives of deacetylation; because with per-cent identical and original unmodified transparent quality bonding, the end article that they form is easier to be dissolved in blood flow.
Know that by the acceptor of CD44 cytolemma, HA regulates many various process relevant with stechiology and biology, as propagation, the differentiation and mobile of cancer cells and other cell.
Recently, scientific literature has shown the anticancer effect of HA when HA is injected directly in the growth of cancer at this point.Verified, can be measured to the degeneration fully of 30% tumour.Know that also HA can combine with various chemotherapeutics, to produce many different pharmaceutical compositions, because it can be as second kind of antitumour drug, the antitumous effect (international patent application no WO 01/47561) of collaborative raising and its medicine linked together; Perhaps, existing people claims that HA self can be used as a kind of anticarcinogen that uses in different clinical protocol, is used to suppress/growth (international patent application no WO 97/40841) of retrograde cancer.
The Taxan of existing and HA or HA derivative covalent bonding, as mentioned above, all different with all prescriptions of Taxan, especially with the covalent attachment of the taxol of HA or HA derivative, randomly by spacer molecule, it is water-soluble that taxol is become, and do not influence drug effect.
In fact, described in the embodiment 1 in vivo experiment showed, that the taxol of puting together of the present invention has identical anticancer effect with the non-taxol of puting together when the dosage that uses is identical.
In addition, the HA taxol can show unexpected pharmacology performance, and these performances are different with the pharmacology performance of the non-taxol of puting together, especially in the tumour of some type.
In fact, embodiment 2 has clearly illustrated that the ester derivative of of the present invention and paclitaxel bonded HA has new antitumor pharmacological activity: in the described below vitro cytotoxicity model, HA-taxol of the present invention shows amazing antitumour activity, considerably beyond the independent non-taxol of puting together.
New antitumor characteristic means, Taxan of the present invention, especially after taxol and HA or HA derivative are puted together, can be used for the preparation of pharmaceutical composition as a kind of chemotherapeutics, it is not only useful to the various forms of tumours of using the Tyke rope, and for usually the tumour without other form of Tyke rope treatment is also useful, as cancer of the stomach and liver cancer, colorectal carcinoma, melanoma cancer and leukemia.In addition, it can also be used for systemic autoimmunity imbalance, as rheumatoid arthritis, systemic lupus erythematous, autoimmune glomerulonephritis, and this change of bridge thyroiditis thyroiditis.
Using product of the present invention in above-mentioned disease is possible as new pharmacological treatment, because new HA-taxol compound has reduced Tyke rope (Taxol
) systemic toxicity, like this, just increased the result of treatment of medicine itself because it is:
-water miscible;
-not with polyoxyethylenated castor oil (Cremophor
El) combination, the toxicity that therefore these goods did not produce;
The dosage that-dosage is significantly less than or equals to use in the general clinical protocol, and effect is identical;
Also know in addition,, generally also be used to reduce the restenosis after angioplasty (being generally artery), crown bridging and the organ transplantation as the drug use taxol.
Taxan of the present invention, especially behind taxol and HA or the HA derivative covalent bonding, also can be used for preventing restenosis, perhaps can be used for above-mentioned postangioplasty, form the support of transplanting and the undercoat of device, because proved it can Chemical bond on the surface of described support, and be easy to be adsorbed on above them.
In both cases, the residence time of goods of the present invention on rack surface, and the release gradually in blood flow thus, greater than the non-taxol of puting together, but because the physicochemical property of HA help progressive, discharge Tyke rope (Taxol from the surface of device continuously slowly
).
Contain with the pharmaceutical composition of the Taxan of the present invention of HA or HA derivative covalent bonding can the whole body administration, (by intravenously, intra-arterial, intraperitoneal, intramuscular, subcutaneous or path, oral cavity), it also is used for topical application (passing through Transdermal absorption), perhaps puts administration by being injected directly into cancer location.
HA or derivatives thereof self with the taxol covalent bonding also can be used as a kind of cancer therapy drug.
In the following example 3, the applicant has proved HA, ACP
Cross-linked derivant, be how to handle the intravital experimental growth of tumor of bringing out of nude mice, thereby compare the obvious degeneration of having measured tumour with non-processing contrast.
Therefore, the applicant has described to constitute HA and the HA derivative of goods Taxan-HA of the present invention or Taxan-HA derivative for the first time, as a kind of new role of antitumour drug and they use in oncology.
In addition, the Taxan of of the present invention and HA or HA derivative covalent bonding can be united use with various biology and pharmacological activity molecule (for example: steroid, hormone, protein, nutrient substance, VITAMIN, non-steroidal anti-inflammatory drug, chemotherapeutics, calcium antagonists, microbiotic, antiviral agent, interleukin and cytokine such as Interferon, rabbit).
By this method, may obtain the difference combination of said medicine and the corresponding different pharmaceutical composition that contains the Taxan of this invention.
This invention also relates to Taxan of the present invention, the reparation technology of taxol and HA or HA derivative covalent bonding especially, and goods of the present invention can obtain by following technology:
1) relate to Taxan and HA or HA spread out introduce between this thing spacer (molecule) between be bonded into, or
2) directly synthetic between Taxan and HA or HA derivative.
The HA that can react by the method and the taxol of direct or indirect spacer molecule or the functional group of HA derivative are as follows:
1) hydroxyl;
2) carboxyl;
3) remove the amino of acetyl HA.
For example, spacer molecule (base) can be selected from aliphatics or araliphatic (araliphatic) chain (straight or branched), by one or more hydroxyl, carboxyl or carbonyl, epoxide, acyl chlorides, mercaptan, nitro, halogen, acid anhydride, isocyanic ester and lsothiocyanates of being selected from, and amino the replacement.
In possible spacer molecule, contain 2 to 18 carbon atoms, especially those carboxylic acid bromides that contain 3 to 10 carbon atoms are preferably; 3-bromo-propionic acid and 4-bromo-butyric acid are then better.
The sense regiment headquarters hydroxyl of HA or HA derivative and such as the building-up reactions between the Taxan compositions such as taxol can obtain by direct or indirect synthetic technology.
Between be bonded into the covalent linkage that may cause between spacer molecule and HA or HA derivative forming following type:
Ester bond:
-comprising the carboxyl functional group of the spacer molecule of suitable selection, spacer molecule is by activators such as carbodiimide activation (following scheme 1);
-comprise the hydroxyl of HA or HA derivative, bromination or replace with tosyl group, the carboxyl of the spacer molecule by suitable selection carries out nucleophilic substitution (following scheme 2) then; Or
-comprise the anhydridization functional group (following scheme 3) of the spacer molecule of suitable selection.
Scheme 1-2-3
Urethanum (urethane) or thioxanthamide key:
-comprise the amino (following scheme 4) of the spacer molecule of suitable selection;
-comprise the isocyanic ester or the lsothiocyanates functional group (following scheme 5) of the spacer molecule of suitable selection.
Scheme 4-5
Ehter bond:
-comprise the epoxy-functional (following scheme 6) of the spacer molecule of suitable selection
-comprising bromination or the HA that replaces with tosyl group or the hydroxyl of HA derivative, the hydroxyl of the spacer molecule by suitable selection carries out nucleophilic substitution (following scheme 7) subsequently.
Scheme 6-7
Acetal bonds or ketal key:
-comprise suitable selection spacer molecule acetaldehyde and (or) ketone group (following scheme 8);
-comprise the hydroxyl of the spacer molecule of suitable selection, and need the existence of simple carbonyl compound, as: formaldehyde (following scheme 8).
Scheme 8
Scheme 9
Can use activator, for example, activate the hydroxyl of HA or HA derivative, carry out above-mentioned technological process from being selected from carbonyl dimidazoles and two-(N-succinimido) (di-(N-succimidy1)) carbonic ether.
Direct building-up reactions between the hydroxyl of HA or HA derivative and the Taxan (as: taxol) can cause the formation of following class shape covalent linkage:
Acetal bonds:
-comprising the hydroxyl of Taxan and the hydroxyl of HA or HA derivative, they realize covalent bonding (scheme 10) by the addition of a simple carbonyl compound (as: formaldehyde).
Scheme 10
Reaction between the carboxyl of the derivative of HA or HA and the Taxan (as: taxol) can obtain by direct or indirect synthetic method.
Between be bonded into the covalent linkage that may cause between spacer molecule and HA or HA derivative forming following type:
Ester bond:
The carboxyl of-suitable the spacer molecule of selecting, as: 4-bromo-butyric acid (4-bromobutyric acid) by the activation of activators such as carbodiimide, like this, just is applicable to the hydroxyl synthetic (being preferably on the carbon of C2 ' position) with Taxan (as: taxol).Subsequently, directly contact, obtain the nucleophilic substitution of the carboxyl of HA or HA derivative the bromine of spacer molecule by quaternary ammonium salt in anhydrous solvent especially tetrabutylammonium (TBA) salt.Like this, form the ester bond between HA or HA derivative and the spacer molecule, then with paclitaxel bonded.Perhaps, the carboxyl of HA or HA derivative can occur in (following scheme 11) before the key of spacer molecule itself and Taxan to the nucleophilic substitution of the bromine of spacer molecule.
-the activator (as: carbodiimide) of carboxyl by using HA or HA derivative may form ester bond between the hydroxyl of described group and the suitable spacer molecule of selection, spacer molecule or in advance or afterwards with paclitaxel bonded (following scheme 12).
Scheme 11-12
Amido linkage:
The carboxyl of-HA or HA derivative can be connected (but except all hydrazides) with the amino of suitable selection spacer molecule by the activation of activator, in advance or afterwards with Taxan bondings (following scheme 13) such as taxols.
Scheme 13
The directly synthetic formation that can cause the covalent linkage of following type:
Ester bond:
The carboxyl of-HA or HA derivative can make it and the hydroxyl of Taxan link (following scheme 14) by the activation of activator;
The hydroxyl of-Taxan composition can make it and the carboxyl of HA or HA derivative link (scheme 14) by the activation of activator;
Scheme 14
The key of-following type needs the bromide or the tosylate of Taxan.Described key is produced (scheme 15) by bromide or tosylate by the nucleophilic substitution of the carboxyl of HA or HA derivative.
Scheme 15
Go the amino of acetyl HA and the building-up reactions between the Taxan composition (as: taxol), can realize by direct or indirect synthesis technique.
The indirect synthetic covalent linkage that can cause between spacer molecule and HA, forming following type:
Amido linkage:
-comprise the carboxyl (scheme 16) of the spacer molecule of suitable selection;
Scheme 16
Urethanum or thioxanthamide key:
-comprise the hydroxyl or the sulfydryl (thiolic) (scheme 17) of the spacer molecule of suitable selection.
Scheme 17
The directly synthetic formation that can cause the covalent linkage of following type:
Urethane bonds (urethane bond):
-comprise the hydroxyl of Taxan and remove the amino (scheme 18) of acetyl HA.
Scheme 18
Equally, the key that comprises Taxans such as spacer molecule and taxol, can be ester (scheme 19), urethanum or thioxanthamide (scheme 20), acetal or ketal class (scheme 21), may need the existence of activator, especially for ester and urethane bonds.
Scheme 19
Scheme 21
Before or after spacer molecule can link in the functional group with HA or HA derivative, with Taxan bondings such as taxols, this depended on the type of functional group of the spacer molecule of suitable selection.
The per-cent direct or indirect link of Taxan (as: taxol) and HA or HA derivative can change between 0.1% and 100%, is preferably between 0.1% and 35%.Provide the following example, provide infinite explanation existing invention.
Embodiment 1
After implanted tumor cells, the new HA and the ester derivative of taxol are in the intravital effect of nude mice
Hereto the experiment, we in belonging to the immunosuppressant nude mouse of athymic CD-1 species, end user's adenocarcinoma ovaries cell, OVCAR-3 cell.
Each mouse all passes through peritonaeum path inoculation 5 * 10
6Individual cancer cells.
Experimental design
Test drug:
-Tyke rope (Taxol
), use for 5 animals
-HYTAD1p20: the ester derivative of HA that the taxol covalent bonding of 16% carboxyl esterification degree (w/w) is arranged.The molecular weight that is used for the HA of synthetic this new drug is 200,000Da (its preparation sees embodiment 7 for details).Also five animals are gone up and use this medicine.
The animal of treatment: 10 animals are at first by inoculation OVCAR-3 cell.5 are used to do Tyke rope (Taxol
)
Experiment
And in addition 5 be used for the HYTAD1p20 experiment:
-all 10 animals are accepted the pharmacological agent (behind the inoculation cancer cells the 6th, 13,20 day) of 3 dosage subsequently by peritoneal injection, dosage is 20mg Tyke rope (Taxol
)/kg body weight or 125mgHYTAD/kg body weight (corresponding to taxol 20mg/ mouse).
Control animal (CONTROL ANIMALS): the cancer that 5 animals have at first inoculated the OVCAR-3 cell is brought out suspension, then, does not accept any treatment.
Determining of survivorship curve
The date 92nd day calculating of survivorship curve from behind intraperitoneal prevention cancer cells, beginning to intervene.
The result: the result of acquisition is as shown in Figure 1.
Three control animals got adenocarcinoma ovaries, and dead between 70-75 days behind the transplanting cancer cells.After intervention the 92nd day, i.e. Shi Yan the last day, the animal of accepting taxol or HYTAD pharmacological agent does not have a death.
Example 2
External experiment
In vitro Shi Yan purpose mainly is to determine the activity curve with paclitaxel bonded new HA ester derivative, and the anti-tumor activity compared with taxol of evaluations/comparison HYTAD derivative, thus definite medicine potential that they are compared with antitumor drug.
Experimental design:
Test article:
-Tyke rope Taxol
: with reference to goods
-HYTAD1p20-HYTAD2p20-HYTAD2p10: with the ester derivative of the HA of taxol covalent bonding, 16% carboxyl esterification degree (w/w) (if HYTAD1p20 is arranged, being used for new drug synthetic HA molecular weight is 200,000Da) (its preparation sees embodiment 7 for details) or 22% (if HYTAD2p20, employed HA molecular weight is 39,000Da), and perhaps 6.8% (if HYTAD2p10, employed HA molecular weight is 39,000Da).
Clone
The clone in people source
Four MCF-7 have been used.All four experimental cell strains generally all respond to taxol, and the identical amplification degree expressed receptor CD44 on apparent.
-
MCF-7
-
MDA-MB-231
-
MDA-MB-468
-
SKBR-3
Experimental program:
1) put test cell system in 96 flat orifice plates, concentration is 3000 cells in every hole:
2) after 24 hours, be used in the test soln that suitably dilutes in the substratum and replenish cell;
3) after spending 72 hours, with 3-(4,5-dimethyl-2-thiazolyl)-2,5-phenylbenzene-2H-tetrazolium bromide (MTT) is tested with colorimetry test pair cell; By the viability of assessment cell, this test has also disclosed the different susceptibility of cell to testing drug.This is possible, because mitochondrial dehydrogenase can be reduced to tetrazolium salts (yellow) the first crystal of blue look.The size of colour intensity is used spectrophotometry (Dezinot F. etc., J.Immunol Methods, 1986,22 (89): 271-277).
The result:
Below, we will be with the form of form among Fig. 2 and chart, with term IC
50Result (the IC that report obtains
50For for the test article and different clones used, suppress 50% the required drug level of cell enlargement).
Among Fig. 2, axis of abscissa represents that drug effect is (with IC
50And be calculated as molconcentration and with reference to the ratio between the goods (taxol), the latter has one 0 value as usual expression).Therefore, deshed line is represented the drug effect greater than the reference goods.
IC
50(taxol or its HYTAD derivative in the substratum of representing with nM or μ M)
| Clone | Tyke rope (Taxol ) | HYTAD2p20 | HYTAD1p20 | HYTAD2p10 |
| Breast cancer cell line | ||||
| MCF/7 | 3.5nM | 0.86nM | 0.024nM | 0.68nM |
| MDA/MB/231 | 0.35nM | 2.58nM | --- | 0.24μM |
| MDA/MB/468 | 9.4nM | --- | 0.18nM | --- |
| SKBR/3 | 0.23nM | --- | --- | 0.14nM |
Conclusion
According to reported literature, the clone of all uses is all to Tyke rope sensitivity, and the Tyke rope is the metastatic carcinoma that is mainly used in treatment mammary gland and ovary.About breast cancer cell line, various HYTAD confirm more much better than than taxol, and for cancerous cell line MCF-7, the coefficient of HYTAD1p20 is+150.
Embodiment 3
After implanted tumor cells, the effect of the intravital ACP gel of nude mice.
Experiment hereto, we are end user's colorectal carcinoma HT29 cell in the nude mouse that suppresses immunity, genus athymia (nu/nu) species.
Each animal is all anaesthetized, and injection 0.3ml concentration is the HT29 cell suspending liquid of 166,000 cells/ml in its peritoneal cavity.Like this, each mouse is accepted 50,000 cancer cells.
Experimental design:
The animal of treatment:113 animals at first inoculate HT29, and immediately accept the ACP gel that potion 0.2ml concentration is 40mg/ml;
Control animal: 117 animal inoculation pvaccinations HT29 cancer cells suspension, but do not receive treatment.
Survivorship curve: survivorship curve is from calculated by dead day inoculation day.From the weight loss of beginning confirm the death of animal 20% or more and under the situation of hemoperitoneum of expression diffusion transfer or with its execution.Measure the survival rate in two groups every day, and express, with the curve that obtains to be reported among Fig. 3 with chart.
This Therapy lasted 120 days, subsequently, with the sacrifice of animal and the autopsy of all survivals, to check existing of abdominal tumor.
The result: there are 32 animals not form tangible tumour in 230 animals.There are 22 to belong to and use ACP in these animals
The mouse group of gel for treating has 10 to belong to control group.
ACP
Gel: 19.5% treatment animal does not develop into tumour;
Contrast: 8.5% control animal does not develop into tumour.
Embodiment 4
Molecular weight is the preparation (for may synthesizing of HA-taxol and lower molecular weight HA) of the HA between 5,000 and 10,000 dalton
2.40gHA sodium, molecular weight are 990,000Da is dissolved in the 0.15M NaCl solution of 240ml.Replenish with 7.9ml 14%NaOCl solution then.Under+4 ℃ steady temperature, solution is at 20Hz, and 150W uses sonic treatment 120 minutes.In case reaction finishes, and pH is adjusted to 6.5 with 0.1N HCl, in methanol-acetone mixt precipitates at 2: 1 at 1000ml then.Filter and collect goods at 45 ℃, by 48 hours vacuum-drying.So just obtain the 1.65g sodium salt.The analytical results of high pressure liquid chromatography (HPLC) (HPLC)-GPC shows that the molecular-weight average (MW) of the HA part of acquisition is 5,850, and number-average molecular weight (MN) is 3640, and heterogeneity index is 1.61.
Embodiment 5
With the preparation of the ester derivative of paclitaxel bonded HA, the carboxyl esterification degree is dissolved in CH for about 4%w/w51mg taxol
2Cl
2In, use 104mg 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) and 20mg 4-bromo-butyric acid make-up solution then.Then, solution is distributed in water.After removing carbodiimide and bromide resistates, use the anhydrous sodium sulfate drying reaction solvent, and it is removed with rotatory evaporator.Like this, the 21mg goods of acquisition just are dissolved in n-methyl-pyrrolidone (NMP), add the HA solution with the tetrabutylammonium salinization of 20mg/ml.(TBA) among the NMP (200mg among the 10mlNMP).After 7 days reaction at room temperature takes place, with solution with 5ml water and the saturated NaCl solution dilution of 1ml.With the solution stirring that so obtains 1 hour, so that sodium and TBA ion exchange.Then, once add an ethanol at leisure, the thread goods of Huo Deing dissolve in water, dialyse and be final through freeze-drying like this.
Embodiment 6
Prepare the ester derivative of HA, the about 10%w/w of the gamma value of carboxyl with taxol
The same with embodiment 5, the taxol with 308.7mg is dissolved in the methylene dichloride of 15ml replenishes with 117.2mg4-bromo-butyric acid and 614.1mg EDC.Then, water is added this solution, to remove all bromides and carbodiimide.The organic solution that so obtains is replenished dehydration with sodium sulfate, getting rid of solution with rotatory evaporator.Finally, obtain the intermediate of 363mg.
In the 175mg intermediate that so obtains, add 1g dissolved HA-TBA in anhydrous NMP.This solution was at room temperature stirred 7 days, then, add 20ml water and the saturated NaCl solution of 4ml.This was stirred 1 hour, so that sodium and TBA ion exchange.Then, once add an ethanol at leisure, the thread goods of Huo Deing dissolve in water, dialyse and be final through freeze-drying like this.
Prepare the ester derivative of HA, the about 16%w/w of the gamma value of carboxyl with taxol.
In the 164mg intermediate that obtains by the program described in front embodiment 5 and the example 6, add the solution that 680mg HA-TBA is dissolved in the anhydrous NMP of 25ml.After 7 days reaction at room temperature takes place, solution is replenished with the water of 20ml and the saturated NaCl solution of 4ml.After 1 hour, once add an ethanol at leisure.So the goods that obtain are collected by filtering, dissolving in water, dialysis then, and drop to 10 μ S when following when the electroconductibility of dialyzate, it is solidified.The solution freeze-drying that to solidify then.
Embodiment 8
Prepare the HA ester derivative with taxol, the gamma value of carboxyl is about 10%w/w
102.6mg taxol be dissolved in the methylene dichloride of 5ml, solution is replenished with the 20.4mg succinyl oxide.After three hours, solution evaporation is removed by using rotatory evaporator.So the goods that obtain are dissolved in the dimethyl sulfoxide (DMSO) (DMSO) of 5ml low water content, and add 27.3mg dicyclo-hexyl-carbodiimide.After about 5 minutes, the HA-TBA solution that is used in dimethyl sulfoxide (DMSO) (DMSO) the dissolving 327mg polymkeric substance acquisition of 15ml low water content replenishes this solution.At room temperature, with about 24 hours of solution stirring.Then, in this solution, add number ml water and the saturated NACL solution of 3ml.After 1 hour, it is precipitated by adding ethanol.Like this, in water, dissolve, dialyse and final freeze-drying by filtering the thread goods of collecting.
Embodiment 9
With the ester derivative of the HA of taxol preparation, the gamma value of carboxyl is about 4%w/w
510.1mg be dissolved in the taxol of 6ml dichloromethane, replenish with 95.4mg 3-3-bromine first propionic acid and 525.0mg EDC.Then, in this solution, add entry, be equipped with by branch and remove bromide and carbodiimide, and use the water of 10 times of amounts to remove these reagent.Organic solution is replenished with sodium sulfate, with its dehydration, and will remove solvent with rotatory evaporator.
Add the HA-TBA that 1.46g is dissolved in anhydrous NMP in the 155.5mg intermediate that so obtains, the solution of Huo Deing at room temperature stirred 7 days like this.Then, add 20ml water and the saturated NaCl solution of 4ml.With this solution stirring 1 hour, so that sodium and TBA ion exchange.Then, once add an ethanol at leisure, the thread goods of Huo Deing dissolve in water, dialyse and be final through freeze-drying like this.
Embodiment 10
The preparation of hyaluronic ester derivative, the gamma value of carboxyl is about 30%w/w
The 500mg taxol is dissolved in CH
2Cl
2In, use 397.6mg 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) and 300.9mg 4-bromo-butyric acid make-up solution then.Then, solution distributes in water.In case carbodiimide and bromide resistates are removed, with anhydrous sodium sulphate with the reaction solvent drying, and with rotatory evaporator with removal of solvents.The goods that so obtain are dissolved among the NMP, add and contain the hyaluronic solution that the TBA salt among have an appointment 20mg/ml and the NMP closes approximately.(1.95g among the 100ml NMP).After 7 days reaction at room temperature takes place, add 20ml water and the saturated NaCl solution of 4.5ml and dilute.With this solution stirring 1 hour, so that sodium and TBA ion exchange.Then, once add an ethanol at leisure, the thread goods of Huo Deing dissolve in water, dialyse and be final through freeze-drying like this.
Embodiment 11
The preparation of the ester of the part self-crosslinking of HA (about 10% substitution value), taxol w/w is 8%.
3.10g the HA with the TBA salinization at room temperature is dissolved among the DMSO of 150ml low water content.Replenish according to the middle taxol that embodiment 5,6 and 7 described methods are obtained with 541.0mg then.After at room temperature reacting 7 days, with 126.5g triethylamine postreaction solution, then with whole stirring 30 minutes.319.5g 2-chloro-1-methyl-pyrimidine iodide are dissolved in the resulting solution of 30ml DMSO slowly add one, allow mixture keep 15 hours down at 30 ℃ with timed interval of 45 minutes.Adding is slowly poured the mixture that is obtained into the acetone of 400ml then by the solution that 50ml water and 1.7g sodium-chlor are obtained, and constantly stirs simultaneously.The sedimentation and filtration that forms is also washed three times with 5: 1 acetone of 50ml, and it is inferior to give a baby a bath on the third day after its birth with 50ml acetone again.With the end article that so obtains 38 ℃ of vacuum-dryings.
Embodiment 12
The test of the solubleness of HA-taxol in 5% glucose solution that obtains according to embodiment 5.
To be dissolved in the D/W of 1ml 5% according to HA-taxol system (the carboxyl substituted degree the is 16.3%w/w) 14.6mg that the esterification of embodiment 7 (is that the HA of 200kDa begins from molecular weight) obtains.Solution with magnetic stirring bar stirs can filter by the 0.20 μ m sterilizing filter that is installed on the syringe.Taxol concentration in solution is 2.38mg/ml.
We also try to find out in the glucose sugar aqueous solution of every 1ml 5%, the peak concentration of goods.Contain in the 1ml glucose solution under the concentration of 32.8mg HA-taxol goods, obtain viscous soln, taxol concentration is 5.35mg/ml.
Embodiment 13
From human plasma, reclaim the test of taxol
Be dissolved in the resulting solution of 10ml water with 101.3mg HA-taxol.Described in embodiment 7, preparation HA-taxol.
Above-mentioned solution of 40mg and 2ml human plasma are come in contact at 37 ℃, reclaim experiment.
In order to measure, are set: 6,30 and 60 minutes three other duration of contact by taxol self is separated the taxol that is discharged into the blood plasma from HA.Terminal point in each contact interval, from wash blood plasma-HA-paclitaxel solution of three times, extract taxol, each with 1.5ml t-butyl methyl ether (TBME), it is collected together, spontaneous evaporation is to doing in 65 ℃ of environment, and in 40 μ l dehydrated alcohols, form suspension again, to measure the content of drug of being discussed by HPLC (high pressure liquid chromatography (HPLC)).The result who obtains as shown in Figure 4.After 6 minutes, the taxol more than 80% separates with HA, and then, in observation after this, this per-cent no longer increases.
For described invention, these methods can be improved by different modes obviously.Such improvement is not considered to depart from the spirit and the purpose of invention, and very well-known this type of improvement for the expert in this field will be discussed in the claim below.
Claims (73)
1. with the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding; it is characterized in that; covalent linkage is at the hydroxyl of Taxan and the carboxyl or the hydroxyl of hyaluronic acid or derivatives of hyaluronic acids; perhaps form between the hyaluronic amino of deacetylate; randomly Taxan is connected on hyaluronic acid or the derivatives of hyaluronic acids, but that condition is described spacer molecule is different with hydrazides by spacer molecule.
2. according to the Taxan of claim 1, it is characterized in that Taxan is selected between taxol and the Docetaxel and chooses.
3. according to the Taxan of claim 1, it is characterized in that described Taxan is a taxol.
4. according to the Taxan of claim 1, it is characterized in that described hyaluronic molecular weight is 400 to 3 * 106 dalton.
5. according to the Taxan of claim 4, it is characterized in that described hyaluronic molecular weight is 400 to 1 * 106 dalton.
6. according to the Taxan of claim 4, it is characterized in that described hyaluronic molecular weight is 400 to 230,000 dalton.
7. according to the Taxan of claim 1, it is characterized in that, described hyaluronic acid with organic bases and (or) the mineral alkali salify.
8. according to the Taxan of claim 1, it is characterized in that described derivatives of hyaluronic acids is selected from the ester that the alcohol of hyaluronic acid and aliphatics, araliphatic, alicyclic, aromatic series, ring-type and heterocyclic series forms, the gamma value of described ester is equal to or less than 50%.
9. according to the Taxan of claim 1, it is characterized in that, described derivatives of hyaluronic acids is selected from the acid amides that the amine of hyaluronic acid and aliphatics, araliphatic, alicyclic, aromatic series, ring-type and heterocyclic series forms, and the amidation degree of described acid amides is between 0.1% to 10%.
10. according to the Taxan of claim 1, it is characterized in that described derivatives of hyaluronic acids is selected from hyaluronic O-sulfated derivative, degree of sulfation is up to the 4th degree.
11. the Taxan according to claim 1 is characterized in that, described derivatives of hyaluronic acids is selected from gamma value and is equal to or less than 15% hyaluronic acid lactone.
12. the Taxan according to claim 1 is characterized in that, described derivatives of hyaluronic acids is selected from the hyaluronic acetyl product that takes off, and it is from unitary deacetylated the obtaining of N-acetylglucosamine thoroughly, and degree of deacetylation is between 0.1% and 30%.
13. the Taxan according to claim 1 is characterized in that, described derivatives of hyaluronic acids is selected from hyaluronic full carboxylation derivant, and its oxidation from the unitary primary hydroxyl of N-acetylglucosamine makes, and full carboxylation degree is between 1 and 100%.
14. the Taxan according to claim 1 is characterized in that, described covalent linkage forms between the hydroxyl of the hydroxyl of Taxan and hyaluronic acid or derivatives of hyaluronic acids.
15. the Taxan according to claim 1 is characterized in that, described covalent linkage forms between the carboxyl of the hydroxyl of Taxan and hyaluronic acid or derivatives of hyaluronic acids.
16. the Taxan according to claim 1 is characterized in that, described covalent linkage is at the hydroxyl of Taxan and take off between the hyaluronic amino of acetyl and form.
17. Taxan according to claim 1, it is characterized in that, Taxan is connected to spacer molecule on hyaluronic acid or the derivatives of hyaluronic acids, be selected from aliphatics or araliphatic chain (straight or branched), replaced by one or more hydroxyl, carboxyl, carbonyl, epoxide, acyl chlorides, mercaptan, nitro, halogen, acid anhydride, isocyanic ester, lsothiocyanates and amino of being selected from.
18. the Taxan according to claim 17 is characterized in that, spacer molecule is selected from the aliphatics with 2-18 carbon atom or the carboxylic acid of araliphatic chain, and it is replaced by bromine.
19. the Taxan according to claim 17 is characterized in that, spacer molecule is selected from the aliphatics with 3-10 carbon atom or the carboxylic acid of araliphatic chain, and it is replaced by bromine.
20. the Taxan according to claim 17 is characterized in that, spacer molecule is selected from 3-bromo-propionic acid and 4-bromo-butyric acid.
21. the Taxan according to claim 1 is characterized in that, covalent linkage is the ester bond between the hydroxyl of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids.
22. the Taxan according to claim 1 is characterized in that, covalent linkage is at the spacer molecule of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids and amino-formate bond between the hydroxyl or thioxanthamide key.
23. the Taxan according to claim 1 is characterized in that, covalent linkage is the ehter bond between the hydroxyl of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids.
24. the Taxan according to claim 1 is characterized in that, covalent linkage is acetal bonds or the ketal key between the hydroxyl of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids.
25. the Taxan according to claim 1 is characterized in that, covalent linkage is the acetal bonds between the hydroxyl of the hydroxyl of hyaluronic acid or derivatives of hyaluronic acids and Taxan.
26. the Taxan according to claim 1 is characterized in that, covalent linkage is the ester bond between the carboxyl of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids.
27. the Taxan according to claim 1 is characterized in that, covalent linkage is the amido linkage between the carboxyl of spacer molecule and hyaluronic acid or derivatives of hyaluronic acids.
28. the Taxan according to claim 1 is characterized in that, covalent linkage is the ester bond between the hydroxyl of the carboxyl of hyaluronic acid or derivatives of hyaluronic acids and Taxan.
29. the Taxan according to claim 1 is characterized in that, covalent linkage is the amido linkage between spacer molecule and the hyaluronic amino that takes off acetyl.
30. the Taxan according to claim 1 is characterized in that, covalent linkage is amino-formate bond or the thioxanthamide key between spacer molecule and the hyaluronic amino that takes off acetyl.
31. the Taxan according to claim 1 is characterized in that, covalent linkage is the carboxylamine key that takes off between the hydroxyl of the hyaluronic amino of acetyl and Taxan.
32. Taxan according to Claim 8 is characterized in that, hyaluronic acid esterification after forming covalent linkage with Taxan.
33. the Taxan according to claim 11 is characterized in that, hyaluronic acid esterification after forming covalent linkage with Taxan.
34. the Taxan according to claim 1 is characterized in that, covalent linkage is the ester bond between Taxan and the spacer molecule.
35. the Taxan according to claim 1 is characterized in that, covalent linkage is amino-formate bond or the thioxanthamide key between Taxan and the spacer molecule.
36. the Taxan according to claim 1 is characterized in that, covalent linkage is acetal bonds or the ketal key between Taxan and the spacer molecule.
37. the Taxan according to claim 1 is characterized in that, the key per-cent of hyaluronic acid and Taxan is between 0.1% and 100%.
38. the Taxan according to claim 37 is characterized in that, the key per-cent of hyaluronic acid and Taxan is between 0.1% and 35%.
39. the Taxan according to claim 1 is characterized in that, hyaluronic acid or derivatives of hyaluronic acids have improved the antitumous effect of Taxan.
40. the Taxan according to claim 11 is characterized in that, hyaluronic lactone has improved the antitumous effect of Taxan.
41. the Taxan according to claim 26 is characterized in that, hyaluronic acid has improved the antitumous effect of Taxan.
42. the Taxan that comprises at least a that define and hyaluronic acid or derivatives of hyaluronic acids covalent bonding in claim 1-41 is as active substance, and the pharmaceutical composition of pharmaceutically acceptable vehicle and thinner.
43. the pharmaceutical cpd according to claim 42 is characterized in that, by mode administrations such as oral, intravenously, intra-arterial, intramuscular, subcutaneous, intraperitoneal or transdermals, or is injected directly into tumor locus.
44. the pharmaceutical composition according to claim 42 is characterized in that, by oral mode of entrance administration.
45. the pharmaceutical composition according to claim 42 is characterized in that, hyaluronic acid or derivatives of hyaluronic acids can be discharged into medicine-feeding part with Taxan.
46. the pharmaceutical composition according to claim 42-45 is characterized in that, also comprises one or more biology or pharmacological active substance.
47. pharmaceutical cpd according to claim 46, it is characterized in that described biology or pharmacological active substance are chosen certainly: steroid, hormone, nutrient substance, protein, VITAMIN, non-steroidal anti-inflammatory drug, chemotherapeutics, calcium channel blocker, microbiotic, antiviral drug, interleukin and cytokine.
48. the pharmaceutical cpd according to claim 46 is characterized in that, described biology or pharmacological active substance are Interferon, rabbit.
49. use claim 1-41 definition with Taxan hyaluronic acid or derivatives of hyaluronic acids covalent bonding, it is characterized in that, be used to prepare the purposes of the useful pharmaceutical composition of oncotherapy.
50. use according to claim 49, it is characterized in that, tumor treatment comprise mammary cancer, ovarian cancer and (or) carcinoma of endometrium, melanoma, lung cancer, liver cancer, prostate gland and (or) bladder cancer, cancer of the stomach and (or) chemotherapy of intestinal cancer, leukemia and Kaposi.
51. use claim 1-41 definition with Taxan hyaluronic acid or derivatives of hyaluronic acids covalent bonding, be used to prepare purposes to the useful pharmaceutical composition of autoimmunity symptom treatment.
52. use according to claim 51, it is characterized in that described autoimmunity symptom is selected from rheumatic arthritis, struma lymphomatosa, systemic lupus erythematous and autoimmune glomerulonephritis.
53. use claim 1-41 definition with Taxan hyaluronic acid or derivatives of hyaluronic acids covalent bonding, be used to prepare to the useful medicine group of treatment of restenosis and the purposes of thing.
54. use claim 1-41 definition with Taxan hyaluronic acid or derivatives of hyaluronic acids covalent bonding, be used for purposes to the coating of support and medical facilities.
55. support and medical facilities that the Taxan with hyaluronic acid or derivatives of hyaluronic acids covalent bonding that defines with claim 1-41 is coated with.
56. be used to prepare the method (wherein covalent linkage is an ester bond) with the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding, it is characterized in that, said method comprising the steps of:
A) by the hydroxyl of activator activation Taxan, perhaps, activate the carboxyl of hyaluronic acid or derivatives of hyaluronic acids respectively;
B) add hyaluronic acid or derivatives of hyaluronic acids, perhaps, add the Taxan that is dissolved in the appropriate solvent respectively;
C) goods that so obtain of purifying randomly.
57. the preparation method's (wherein covalent linkage is an ester bond) with the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding is characterized in that, said method comprising the steps of:
A ') produces the bromide or the tosylate of Taxan;
B ') by the carboxyl of hyaluronic acid or derivatives of hyaluronic acids, carry out from steps A ') bromide of the Taxan that obtains or the nucleophilic substitution of tosylate;
C ') goods that obtain of purifying randomly.
58. the preparation method's (wherein covalent linkage is urethanum or thioxanthamide key) with the Taxan that takes off the hyaluronan covalent bonding said method comprising the steps of:
D) with the hydroxyl of activator activation Taxan;
E) interpolation is dissolved in and takes off hyaluronan in the appropriate solvent;
F) goods that so obtain of purifying randomly.
59. with preparation method's (wherein covalent linkage is the acetyl key) of the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding, described technology may further comprise the steps:
G) produce the solution that contains hyaluronic acid or derivatives of hyaluronic acids and Taxan that is dissolved in the appropriate solvent;
H) add simple carbonyl compound, as formaldehyde;
I) goods that so obtain of purifying randomly.
60. the spacer molecule by having a carboxyl at least and by the hydroxyl of ester bond link hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
L) carboxyl of activation spacer molecule, possibility elder generation and Taxan bonding;
M) add hyaluronic acid or derivatives of hyaluronic acids;
N) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
61. the spacer molecule by having a carboxyl at least and by ester bond link hydroxyl hyaluronic acid or derivatives of hyaluronic acids is produced the method with the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding, said method comprising the steps of:
L ') replaces the hydroxyl of hyaluronic acid or derivatives of hyaluronic acids with tosyl group or bromide;
M ') adds spacer molecule, possibility elder generation and Taxan bonding;
N ') goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
62. the spacer molecule by having an acid anhydride base at least and by ester bond link hydroxyl hyaluronic acid or derivatives of hyaluronic acids is produced the method with the Taxan of hyaluronic acid or derivatives of hyaluronic acids covalent bonding, said method comprising the steps of:
L ") spacer molecule is added in the solution that contains hyaluronic acid or derivatives of hyaluronic acids;
M ") goods that so obtain of purifying randomly;
N ") with step L ") or M ") these goods and the Taxan that obtain react.
63. the spacer molecule by having an amino at least also connects hydroxyl hyaluronic acid or derivatives of hyaluronic acids by urethane bonds or thioxanthamide key, the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding the side, said method comprising the steps of:
O) by activator, the hydroxyl of activation hyaluronic acid or derivatives of hyaluronic acids;
P) add spacer molecule, possibility elder generation and Taxan bonding;
Q) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
64. the spacer molecule by having an isocyanic ester or lsothiocyanates at least and by urethane bonds or thioxanthamide key link hydroxyl hyaluronic acid or derivatives of hyaluronic acids, the method of the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding, described technology may further comprise the steps:
O ') hyaluronic acid or derivatives of hyaluronic acids are added in the solution that contains spacer molecule, may before with the Taxan bonding;
P ') goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
65. the spacer molecule by having an epoxy group(ing) at least and by ehter bond link hydroxyl hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
R) with may before with the spacer molecule of Taxan bonding, under the situation that acid or basic catalyst are arranged, add in the solution of hyaluronic acid or derivatives of hyaluronic acids;
S) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
66. the spacer molecule by having a hydroxyl at least and by ehter bond link hydroxyl hyaluronic acid or derivatives of hyaluronic acids, the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding method, said method comprising the steps of:
R ') replaces the hydroxyl of hyaluronic acid or derivatives of hyaluronic acids with tosyl group or bromide;
S ') spacer molecule is added to from step R ' under alkaline environment) the goods that obtain;
T ') goods that so obtain of purifying randomly;
U ') with step S ') or T ') goods and the Taxan that obtain react.
67. the spacer molecule by having a carbonyl at least and by acetal bonds or ketal key link hydroxyl hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
V) under acid or alkaline environment, spacer molecule is added in the solution that contains hyaluronic acid or derivatives of hyaluronic acids;
W) goods that so obtain of purifying randomly;
Z) with step V) or the goods and the Taxan that W) obtain react.
68. the spacer molecule by having a hydroxyl at least and by acetal bonds or ketal key link hydroxyl hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
V ') with simple carbonyl compound (for example: formaldehyde) add to a kind of contain hyaluronic acid or derivatives of hyaluronic acids and the solution of spacer molecule in, spacer molecule may before with the Taxan bonding;
W ') goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
69. the spacer molecule by having a hydroxyl at least and by the carboxyl of ester bond link hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
A) activator is added in the solution that contains hyaluronic acid or derivatives of hyaluronic acids;
B) with may before with the spacer molecule of Taxan bonding, add the solution that obtains in the step a) to;
C) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
70. by having at least a halogen (for example: spacer molecule bromine) and by the carboxyl of ester bond link hyaluronic acid or derivatives of hyaluronic acids, the method of the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
A ') will before may with the spacer molecule of Taxan bonding, add in the solution of hyaluronic acid or derivatives of hyaluronic acids;
B ') goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
71. the spacer molecule by having an amino at least and by the carboxyl of amido linkage link hyaluronic acid or derivatives of hyaluronic acids, the method for the Taxan of preparation and hyaluronic acid or derivatives of hyaluronic acids covalent bonding said method comprising the steps of:
D) activator is added in the solution that contains hyaluronic acid or derivatives of hyaluronic acids;
E) will before may with the spacer molecule of Taxan bonding, add the solution that obtains in the step d) to;
F) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
72. the spacer molecule by having a carboxyl at least also takes off the amino of hyaluronan by the amido linkage link, the method for preparing Yu take off the Taxan of hyaluronan covalent bonding said method comprising the steps of:
G) with activator activation may before with the carboxyl of the spacer molecule of Taxan bonding;
H) interpolation contains the solution that takes off hyaluronan;
I) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
73. the spacer molecule by having a hydroxyl at least also takes off the amino of hyaluronan by urethanum or the link of thioxanthamide key, the method for preparing Yu take off the Taxan of hyaluronan covalent bonding said method comprising the steps of:
L) with activator activation may before with the hydroxyl of the spacer molecule of Taxan bonding;
M) interpolation contains the solution that takes off hyaluronan;
N) goods that so obtain of purifying randomly, if before not with the spacer molecule bonding, then react with Taxan.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000271A ITPD20020271A1 (en) | 2002-10-18 | 2002-10-18 | CHEMICAL-PHARMACEUTICAL COMPOUNDS CONSISTING OF TAXAN DERIVATIVES COVALENTLY LINKED TO HYALURONIC ACID OR ITS DERIVATIVES. |
| ITPD2002A000271 | 2002-10-18 | ||
| PCT/EP2003/011239 WO2004035629A2 (en) | 2002-10-18 | 2003-10-10 | Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
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| CN1705683A true CN1705683A (en) | 2005-12-07 |
| CN1705683B CN1705683B (en) | 2010-04-28 |
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| CN200380101570XA Expired - Lifetime CN1705683B (en) | 2002-10-18 | 2003-10-10 | Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives |
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| EP (2) | EP2045270B1 (en) |
| JP (1) | JP4704753B2 (en) |
| KR (1) | KR101076414B1 (en) |
| CN (1) | CN1705683B (en) |
| AT (1) | ATE420117T1 (en) |
| AU (1) | AU2003267441B2 (en) |
| BR (1) | BR0315431A (en) |
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| DE (1) | DE60325760D1 (en) |
| DK (1) | DK1560854T3 (en) |
| ES (2) | ES2320439T3 (en) |
| HK (1) | HK1082753A1 (en) |
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